Small proteins regulate Salmonella survival inside macrophages by controlling degradation of a magnesium transporter

All cells require Mg2+ to replicate and proliferate. The macrophage protein Slc11a1 is proposed to protect mice from invading mi-crobes by causing Mg2+ starvation in host tissues. However, the Mg2+ transporter MgtB enables the facultative intracellular path-ogen Salmonella enterica serovar Typhimurium to cause disease in mice harboring a functional Slc11a1 protein. Here, we report that, unexpectedly, the Salmonella small protein MgtR promotes MgtB degradation by the protease FtsH, which raises the question: How does Salmonella preserve MgtB to promote survival inside macro-phages? We establish that the Salmonella small protein MgtU pre-vents MgtB proteolysis, even when MgtR is absent. Like MgtB, MgtU is necessary for survival in Slc77a7(+)/(+) macrophages, resis-tance to oxidative stress, and growth under Mg2+ limitation con-ditions. The Salmonella Mg2+ transporter MgtA is not protected by MgtU despite sharing 50% amino acid identity with MgtB and being degraded in an MgtR-and FtsH-dependent manner. Surpris-ingly, the mgtB, mgtR, and mgtU genes are part of the same tran-script, providing a singular example of transcript-specifying proteins that promote and hinder degradation of the same target. Our findings demonstrate that small proteins can confer pathogen survival inside macrophages by altering the abundance of related transporters, thereby furthering homeostasis.